Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease

Science Translational Medicine

Volumn 2, Issue 56, 2010, Pages

  Porter, Forbes D ^a   Scherrer, David E ^b   Lanier, Michael H ^b   Langmade, S Joshua ^b   Molugu, Vasumathi ^b   Gale, Sarah E ^b   Olzeski, Dana ^b   Sidhu, Rohini ^b   Dietzen, Dennis J ^b   Fu, Rao ^a   Wassif, Christopher A ^a   Yanjanin, Nicole M ^a   Marso, Steven P ^c   House, John ^c   Vite, Charles ^d   Schaffer, Jean E ^b   Ory, Daniel S ^b  

^a EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT   (United States)

^b WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF MISSOURI KANSAS CITY SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL MARKER; CHOLESTEROL; CHOLESTEROL OXIDATION PRODUCT; OXYSTEROL; UNCLASSIFIED DRUG; CARRIER PROTEIN; MEMBRANE PROTEIN; NPC1 PROTEIN, HUMAN; NPC1 PROTEIN, MOUSE; PROTEIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHOLESTEROL ESTERIFICATION; CONTROLLED STUDY; DIAGNOSTIC VALUE; DISEASE COURSE; DISEASE SEVERITY; FIBROBLAST; HUMAN; HUMAN CELL; METABOLITE; MOUSE; NIEMANN PICK DISEASE; NIEMANN PICK DISEASE TYPE C1; NONHUMAN; PRIORITY JOURNAL; SYMPTOM; ANIMAL; BAGG ALBINO MOUSE; BLOOD; CHEMICAL STRUCTURE; CHEMISTRY; GENETICS; METABOLISM; MOUSE MUTANT; OXIDATION REDUCTION REACTION; PATHOPHYSIOLOGY; SENSITIVITY AND SPECIFICITY;

ANIMALS; BIOLOGICAL MARKERS; CARRIER PROTEINS; CHOLESTEROL; HUMANS; MEMBRANE GLYCOPROTEINS; MICE; MICE, INBRED BALB C; MICE, KNOCKOUT; MOLECULAR STRUCTURE; NIEMANN-PICK DISEASE, TYPE C; OXIDATION-REDUCTION; PROTEINS; SENSITIVITY AND SPECIFICITY;

EID: 78149342830     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3001417     Document Type: Article

References (62)

1. M. T. Vanier, G. Millat, Niemann-Pick disease type C. Clin. Genet. 64, 269-281 (2003).
2. E. D. Carstea, J. A. Morris, K. G. Coleman, S. K. Loftus, D. Zhang, C. Cummings, J. Gu, M. A. Rosenfeld, W. J. Pavan, D. B. Krizman, J. Nagle, M. H. Polymeropoulos, S. L. Sturley, Y. A. Ioannou, M. E. Higgins, M. Comly, A. Cooney, A. Brown, C. R. Kaneski, E. J. Blanchette-Mackie, N. K. Dwyer, E. B. Neufeld, T. Y. Chang, L. Liscum, J. F. Strauss III, K. Ohno, M. Zeigler, R. Carmi, J. Sokol, D. Markie, R. R. O'Neill, O. P. van Diggelen, M. Elleder, M. C. Patterson, R. O. Brady, M. T. Vanier, P. G. Pentchev, D. A. Tagle, Niemann-Pick C1 disease gene: Homology to mediators of cholesterol homeostasis. Science 277, 228-231 (1997).
3. S. Naureckiene, D. E. Sleat, H. Lackland, A. Fensom, M. T. Vanier, R. Wattiaux, M. Jadot, P. Lobel, Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290, 2298-2301 (2000).
4. D. S. Ory, Niemann-Pick type C: A disorder of cellular cholesterol trafficking. Biochim. Biophys. Acta 1529, 331-339 (2000).
5. S. U. Walkley, K. Suzuki, Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim. Biophys. Acta 1685, 48-62 (2004).
6. N.M. Yanjanin, J. I. Vélez, A. Gropman, K. King, S. E. Bianconi, S. K. Conley, C. C. Brewer, B. Solomon, W. J. Pavan, M. Arcos-Burgos, M. C. Patterson, F. D. Porter, Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B, 132-140 (2010).
7. S. L. Sturley, M. C. Patterson, P. Pentchev, Unraveling the sterol-trafficking defect in Niemann- Pick C disease. Proc. Natl. Acad. Sci. U.S.A. 106, 2093-2094 (2009).
8. J. V. Reddy, I. G. Ganley, S. R. Pfeffer, Clues to neuro-degeneration in Niemann-Pick type C disease from global gene expression profiling. PLoS One 1, e19 (2006).
9. S. Zampieri, S. H. Mellon, T. D. Butters, M. Nevyjel, D. F. Covey, B. Bembi, A. Dardis, Oxidative stress in NPC1 deficient cells: Protective effect of allopregnanolone. J. Cell. Mol. Med. 13, 3786-3796 (2009).
10. C. H. Koh, M. Whiteman, Q. X. Li, B. Halliwell, A. M. Jenner, B. S. Wong, K. M. Laughton, M. Wenk, C. L. Masters, P. M. Beart, O. Bernard, N. S. Cheung, Chronic exposure to U18666A is associated with oxidative stress in cultured murine cortical neurons. J. Neurochem. 98, 1278-1289 (2006).
11. J. R. Zhang, T. Coleman, S. J. Langmade, D. E. Scherrer, L. Lane, M. H. Lanier, C. Feng, M. S. Sands, J. E. Schaffer, C. F. Semenkovich, D. S. Ory, Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking. J. Clin. Invest. 118, 2281-2290 (2008).
12. R. Fu, N. M. Yanjanin, S. Bianconi, W. J. Pavan, F. D. Porter, Oxidative stress in Niemann-Pick disease, type C. Mol. Genet. Metab. 101, 214-218 (2010).
13. G. S. Tint, P. Pentchev, G. Xu, A. K. Batta, S. Shefer, G. Salen, A. Honda, Cholesterol and oxygenated cholesterol concentrations are markedly elevated in peripheral tissue but not in brain from mice with the Niemann-Pick type C phenotype. J. Inherit. Metab. Dis. 21, 853-863 (1998).
14. S. K. Loftus, J. A. Morris, E. D. Carstea, J. Z. Gu, C. Cummings, A. Brown, J. Ellison, K. Ohno, M. A. Rosenfeld, D. A. Tagle, P. G. Pentchev, W. J. Pavan, Murine model of Niemann-Pick C disease: Mutation in a cholesterol homeostasis gene. Science 277, 232-235 (1997).
15. S. J. Langmade, S. E. Gale, A. Frolov, I. Mohri, K. Suzuki, S. H. Mellon, S. U. Walkley, D. F. Covey, J. E. Schaffer, D. S. Ory, Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc. Natl. Acad. Sci. U.S.A. 103, 13807-13812 (2006).
16. P. C. Reid, N. Sakashita, S. Sugii, Y. Ohno-Iwashita, Y. Shimada, W. F. Hickey, T. Y. Chang, A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain. J. Lipid Res. 45, 582-591 (2004).
17. L. Bretillon, A. Sidén, L. O. Wahlund, D. Lütjohann, L. Minthon, M. Crisby, J. Hillert, C. G. Groth, U. Diczfalusy, I. Björkhem, Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases. Neurosci. Lett. 293, 87-90 (2000).
18. C. Xie, E. G. Lund, S. D. Turley, D. W. Russell, J. M. Dietschy, Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration. J. Lipid Res. 44, 1780-1789 (2003).
19. E. P. Beltroy, J. A. Richardson, J. D. Horton, S. D. Turley, J. M. Dietschy, Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease. Hepatology 42, 886-893 (2005).
20. M. Axelson, O. Larsson, 27-Hydroxylated low density lipoprotein (LDL) cholesterol can be converted to 7a,27-dihydroxy-4-cholesten-3-one (cytosterone) before suppressing cholesterol production in normal human fibroblasts. Evidence that an altered metabolism of LDL cholesterol can underlie a defective feedback control in malignant cells. J. Biol. Chem. 271, 12724-12736 (1996).
21. S. Dzeletovic, O. Breuer, E. Lund, U. Diczfalusy, Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. Anal. Biochem. 225, 73-80 (1995).
22. D. Lütjohann, O. Breuer, G. Ahlborg, I. Nennesmo, A. Sidén, U. Diczfalusy, I. Björkhem, Cholesterol homeostasis in human brain: Evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc. Natl. Acad. Sci. U.S.A. 93, 9799-9804 (1996).
23. L. Iuliano, F. Micheletta, S. Natoli, S. Ginanni Corradini, M. Iappelli, W. Elisei, L. Giovannelli, F. Violi, U. Diczfalusy, Measurement of oxysterols and a-tocopherol in plasma and tissue samples as indices of oxidant stress status. Anal. Biochem. 312, 217-223 (2003).
24. K. L. Somers, M. A. Royals, E. D. Carstea, M. A. Rafi, D. A. Wenger, M. A. Thrall, Mutation analysis of feline Niemann-Pick C1 disease. Mol. Genet. Metab. 79, 99-103 (2003).
25. C. D. Davidson, N. F. Ali, M. C. Micsenyi, G. Stephney, S. Renault, K. Dobrenis, D. S. Ory, M. T. Vanier, S. U. Walkley, Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS One 4, e6951 (2009).
26. B. Liu, H. Li, J. J. Repa, S. D. Turley, J. M. Dietschy, Genetic variations and treatments that affect the lifespan of the NPC1 mouse. J. Lipid Res. 49, 663-669 (2008).
27. B. Liu, C. M. Ramirez, A. M. Miller, J. J. Repa, S. D. Turley, J. M. Dietschy, Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid. J. Lipid Res. 51, 933-944 (2010).
28. -/- mouse. Proc. Natl. Acad. Sci. U.S.A. 106, 2377-2382 (2009).
29. I. Björkhem, U. Diczfalusy, Oxysterols: Friends, foes, or just fellow passengers? Arterioscler. Thromb. Vasc. Biol. 22, 734-742 (2002).
30. R. C. Murphy, K. M. Johnson, Cholesterol, reactive oxygen species, and the formation of biologically active mediators. J. Biol. Chem. 283, 15521-15525 (2008).
31. J. W. Newman, C. Morisseau, B. D. Hammock, Epoxide hydrolases: Their roles and interactions with lipid metabolism. Prog. Lipid Res. 44, 1-51 (2005).
32. M. K. Cathcart, Regulation of superoxide anion production by NADPH oxidase in monocytes/ macrophages: Contributions to atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 24, 23-28 (2004).
33. S. Chatterjee, Sphingolipids in atherosclerosis and vascular biology. Arterioscler. Thromb. Vasc. Biol. 18, 1523-1533 (1998).
34. K. Iwabuchi, I. Nagaoka, Lactosylceramide-enriched glycosphingolipid signaling domain mediates superoxide generation from human neutrophils. Blood 100, 1454-1464 (2002).
35. M. T. Vanier, Biochemical studies in Niemann-Pick disease. I. Major sphingolipids of liver and spleen. Biochim. Biophys. Acta 750, 178-184 (1983).
36. M. J. Mol, Y. B. de Rijke, P. N. Demacker, A. F. Stalenhoef, Plasma levels of lipid and cholesterol oxidation products and cytokines in diabetes mellitus and cigarette smoking: Effects of vitamin E treatment. Atherosclerosis 129, 169-176 (1997).
37. S. Ferderbar, E. C. Pereira, E. Apolinário, M. C. Bertolami, A. Faludi, O. Monte, L. E. Calliari, J. E. Sales, A. R. Gagliardi, H. T. Xavier, D. S. Abdalla, Cholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus. Diabetes Metab. Res. Rev. 23, 35-42 (2007).
38. D. Alkazemi, G. Egeland, J. Vaya, S. Meltzer, S. Kubow, Oxysterol as a marker of atherogenic dyslipidemia in adolescence. J. Clin. Endocrinol. Metab. 93, 4282-4289 (2008).
39. C. Prunet, J. M. Petit, A. Ecarnot-Laubriet, A. Athias, C.Miguet-Alfonsi, J. F. Rohmer, E. Steinmetz, D. Néel, P. Gambert, G. Lizard, High circulating levels of 7β- and 7α-hydroxycholesterol and presence of apoptotic and oxidative markers in arterial lesions of normocholesterolemic atherosclerotic patients undergoing endarterectomy. Pathol. Biol. 54, 22-32 (2006).
40. A. Diestel, O. Aktas, D. Hackel, I. Hake, S. Meier, C. S. Raine, R. Nitsch, F. Zipp, O. Ullrich, Activation of microglial poly(ADP-ribose)- polymerase-1 by cholesterol breakdown products during neuroinflammation: A link between demyelination and neuronal damage. J. Exp. Med. 198, 1729-1740 (2003).
41. A. Vejux, G. Lizard, Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis. Mol. Aspects Med. 30, 153-170 (2009).
42. H. Liu, T. Wang, K. Huang, Cholestane-3β,5α,6β-triol- induced reactive oxygen species production promotes mitochondrial dysfunction in isolated mice liver mitochondria. Chem. Biol. Interact. 179, 81-87 (2009).
43. D. E. Brown, M. A. Thrall, S. U. Walkley, S. Wurzelmann, D. A. Wenger, R. W. Allison, C. A. Just, Metabolic abnormalities in feline Niemann-Pick type C heterozygotes. J. Inherit. Metab. Dis. 19, 319-330 (1996).
44. W. Yu, M. Ko, K. Yanagisawa, M. Michikawa, Neurodegeneration in heterozygous Niemann- Pick type C1 (NPC1) mouse: Implication of heterozygous NPC1 mutations being a risk for tauopathy. J. Biol. Chem. 280, 27296-27302 (2005).
45. M. T. Vanier, Phenotypic and genetic heterogeneity in Niemann-Pick disease type C: Current knowledge and practical implications. Wien. Klin. Wochenschr. 109, 68-73 (1997).
46. B. Yerushalmi, R. J. Sokol, M. R. Narkewicz, D. Smith, J. W. Ashmead, D. A.Wenger, Niemann-Pick disease type C in neonatal cholestasis at a North American Center. J. Pediatr. Gastroenterol. Nutr. 35, 44-50 (2002).
47. P. Bauer, T. Boettcher, W. Meyer, P. Martus, S. Weiss, R. Oheim, K. Heinze, M. Wittstock, A. Rolfs, Niemann-Pick type C disease (NP-C) is a considerable diagnosis in juvenile and adult-onset psychiatric disorders, paper presented at the Annual Meeting of the American Society of Human Genetics (ASH-G), Philadelphia, PA, 11 to 15 November 2008.
48. M. C. Patterson, D. Vecchio, H. Prady, L. Abel, J. E. Wraith, Miglustat for treatment of Niemann- Pick C disease: A randomised controlled study. Lancet Neurol. 6, 765-772 (2007).
49. J. E. Wraith, J. Imrie, New therapies in the management of Niemann-Pick type C disease: Clinical utility of miglustat. Ther. Clin. Risk Manag. 5, 877-887 (2009).
50. NP-C Guidelines Working Group, J. E. Wraith, M. R. Baumgartner, B. Bembi, A. Covanis, T. Levade, E. Mengel, M. Pineda, F. Sedel, M. Topçu, M. T. Vanier, H. Widner, F. A. Wijburg, M. C. Patterson, Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol. Genet. Metab. 98, 152-165 (2009).
51. M. Sévin, G. Lesca, N. Baumann, G. Millat, O. Lyon-Caen, M. T. Vanier, F. Sedel, The adult form of Niemann-Pick disease type C. Brain 130, 120-133 (2007).
52. A. Honda, K. Yamashita, T. Hara, T. Ikegami, T. Miyazaki, M. Shirai, G. Xu, M. Numazawa, Y. Matsuzaki, Highly sensitive quantification of key regulatory oxysterols in biological samples by LC-ESI-MS/MS. J. Lipid Res. 50, 350-357 (2009).
53. X. Jiang, D. S. Ory, X. Han, Characterization of oxysterols by electrospray ionization tandem mass spectrometry after one-step derivatization with dimethylglycine. Rapid Commun. Mass Spectrom. 21, 141-152 (2007).
54. W. J. Griffiths, Y. Wang, K. Karu, E. Samuel, S. McDonnell, M. Hornshaw, C. Shackleton, Potential of sterol analysis by liquid chromatography-tandem mass spectrometry for the prenatal diagnosis of Smith-Lemli-Opitz syndrome. Clin. Chem. 54, 1317-1324 (2008).
55. NIH protocol 09-CH-0185: Biomarker Validation for Niemann-Pick Disease, Type C: Safety and Efficacy of N-Acetyl Cysteine.
56. S. Ward, P. O'Donnell, S. Fernandez, C. H. Vite, 2-Hydroxypropyl-β- cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease. Pediatr. Res. 68, 52-56 (2010).
57. A. Frolov, K. Srivastava, D. Daphna-Iken, L. M. Traub, J. E. Schaffer, D. S. Ory, Cholesterol overload promotes morphogenesis of a Niemann-Pick C (NPC)-like compartment independent of inhibition of NPC1 or HE1/NPC2 function. J. Biol. Chem. 276, 46414-46421 (2001).
58. A. Frolov, S. E. Zielinski, J. R. Crowley, N. Dudley-Rucker, J. E. Schaffer, D. S. Ory, NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols. J. Biol. Chem. 278, 25517-25525 (2003).
59. M. A. Kaluzny, L. A. Duncan, M. V. Merritt, D. E. Epps, Rapid separation of lipid classes in high yield and purity using bonded phase columns. J. Lipid Res. 26, 135-140 (1985).
60. E. E. Millard, K. Srivastava, L. M. Traub, J. E. Schaffer, D. S. Ory, Niemann-Pick type C1 (NPC1) overexpression alters cellular cholesterol homeostasis. J. Biol. Chem. 275, 38445-38451 (2000).
61. P. A. Krakowiak, C. A. Wassif, L. Kratz, D. Cozma, M. Kovárová, G. Harris, A. Grinberg, Y. Yang, A. G. Hunter, M. Tsokos, R. I. Kelley, F. D. Porter, Lathosterolosis: An inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. Hum. Mol. Genet. 12, 1631-1641 (2003).
62. Acknowlegments: We are grateful to the Hadley Hope Fund and Ed Cutler (Phlebotomy Services International) for their assistance in obtaining samples from control subjects. We also thank A. Mukherjee, C. Tifft, B. Shamburek, and E. Sidransky for non-NPC1 patient samples. We thank A. Bielska for assistance with figure preparation. This study was also supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F.D.P.) and a Bench to Bedside award from the Office of Rare Diseases (F.D.P.). The authors express their appreciation to the families and patients who participated in this study. Funding: This work was performed in the Metabolomics Core at Washington University. The authors received support from the Washington University Specialized Centers of Clinically Oriented Research grants P50 HL083762 (D.S.O.) and RR02512 (C.V.), Dana's Angels Research Trust (D.S.O. and N.M.Y.), and Ara Parseghian Medical Research Foundation (D.S.O., N.M.Y., and C.V.). Support was also provided by P20 RR020643 and P60 DK020579. Human samples were obtained under NIH protocol 06-CH-0186. Author contributions: F.D.P., J.E.S., and D.S.O. planned the studies. M.H.L., D.E.S., and S.J.L. performed the experiments. M.H.L., V.M., and R.S. carried out GC-MS analyses and analysis of data. S.E.G. performed analysis cholesterol esterification and data analysis. D.O. assisted with animal studies. D.J.D. provided reagents. R.F. performed the TEAC assays. J.H. and S.P.M. designed the studies and provided human samples for analysis. C.A.W. carried out cholesterol measurements. C.V. performed the NPC1 cat treatment studies. N.M.Y. was responsible for sample procurement from study subjects. F.D.P., J.E.S., and D.S.O. wrote the manuscript. Competing interests: F.D.P. and D.S.O. have filed a patent entitled "Disease specific biomarkers for NPC disease" covering the use of oxysterols as a diagnostic test or biomarker in NPC. The other authors declare no conflicts of interest.